Abstract The long-term goal of this project is to develop better therapies for respiratory inflammation and allergic asthma. The incidence and prevalence of asthma continues to increase in all age groups despite progress in the development of new treatments. Current clinical practice employs therapeutic strategies to tolerize allergic patients against specific allergens, indicating that pre-existing pathological TH2 responses can be ?reprogrammed or regulated?, resulting, at least in some cases, in permanent cures. We recently identified a subset of murine plasmacytoid DCs (pDCs) that have the capacity to induce tolerance and actively induce regulatory T (Treg) cells (Mucosal Immunology 2012, Allergy 2013, Immunobiology 2015, JACI 2017). These tolerogenic pDC (tolpDC) subsets do not induce features of allergic asthma such as airway hyperreactiviy (AHR) but can instead prevent the development of allergic airway disease in pre-clinical models. Moreover, we preformed a series of gene expression and surface marker studies and successfully identified a homologous population of tolerogenic pDCs in human blood samples. The mechanisms by which these pDC subsets can induce tolerance and promote induction of Treg cells are multi-factorial. In Specific Aim 1, we proposed series of studies to further explore the therapeutic application of tolpDCs and to fully characterize the mechanisms by which tol pDCs induce Treg cells in pre-clinical models of AHR. In Specific Aim 2 we will determine the ontogeny and study the origin and the development of these pDCs, utilizing knock out models of transcriptional factors involve in conventional DCs and/or pDC development and function. Finally in Specific Aim 3, translational studies will be performed to address if function or frequency of tolpDC subsets could be responsible for the development and/or severity of asthma. These studies, based on strong preliminary data, will focus on developing novel therapy for allergic asthma, a major category of asthma, with impaired immunoregulation. In order to achieve these results we have assembled a team including a leading expert in DC biology and the chief of clinical pulmonology to complement our extensive experience in pre-clinical models. The three parts of project will finally be connected by analyzing whether the factors that control the function and homeostasis of tolpDCs, influence the balance between Treg cells and effector T cell responses, leading to the development of novel therapeutic strategies for allergic diseases and asthma.